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XTRAM
Composition
Capsules
Xtram 50 mg capsule
Each capsule contains Tramadol HCl 50 mg
Action
Tramadol is a centrally acting synthetic analgesic of the aminocyclohexanol group with opioid-like
effects. It is not derived from natural sources, nor is it chemically related to opiates. Although preclinical testing has not completely explained the mode of action, at least two complementary
mechanisms appear applicable: binding to µ-opioid receptors and inhibition of re-uptake of
noradrenaline and serotonin. The opioid-like activity of Tramadol derives from low affinity binding of
the parent compound to µ-opioid receptors and higher affinity binding of the principal active
metabolite, O-desmethyltramadol, denoted M1, to µ-opioid receptors. In animal models, M1 is up to
6 times more potent than Tramadol in producing analgesia and 200 times more potent in µ-opioid
binding. The contribution to human analgesia of Tramadol relative to M1 is unknown.
Both animal and human studies have shown that antinociception induced by Tramadol is partially
antagonized by the opiate antagonist naloxone. In addition, Tramadol shown to inhibit re-uptake of
noradrenaline and serotonin in vitro, as have some other opioid analgesics. These latter mechanisms
may contribute independently to the overall analgesic profile of Tramadol.
The analgesic effect is dose-dependent, but the relationship between serum concentrations and
analgesic effect varies considerably between individuals. In one study, the median serum
concentration of Tramadol required for effective post-operative analgesia was 300 ng/mL, with
individual values ranging from 20 to 990 ng/mL
Apart from analgesia, Tramadol may produce other symptoms similar to that of opioids including
dizziness, somnolence, nausea, constipation, sweating, and pruritus. However, Tramadol causes
significantly less respiratory depression than morphine. In contrast to morphine, Tramadol has not
been shown to cause histamine release. At therapeutic doses, Tramadol has no clinically significant
effect on heart rate, left ventricular function, or cardiac index. Orthostatic changes in blood pressure
observed.
Pharmacokinetics
Absorption
Tramadol is rapidly and completely absorbed after oral administration of 50 mg capsules following a
mean absorption delay (t0) of approximately thirty minutes. The absorption half-life (t½) is 23 ± 11
minutes.
Oral administration of Tramadol with food does not significantly affect its rate or extent of
absorption. Therefore, Tramadol can be administered without regard to food.
After repeated oral administration of 50 mg and 100 mg Tramadol capsules at six hourly intervals,
steady state is reached 30 to 36 hours after the first administration and the bioavailability is greater
than 90%.
Distribution
Tramadol is rapidly distributed in the body, with a volume of distribution of 2 - 3 L/kg in young adults.
The volume of distribution is reduced by about 25% in those aged over 75 years. Plasma protein
binding is about 20% and is independent of concentration up to 10 μg/mL. Saturation of plasma
protein binding occurs only at concentrations outside the clinically relevant range.
Tramadol crosses the placental and blood-brain barriers. Very small amounts of Tramadol and M1 are
found in breast milk (0.1% and 0.02% respectively of the administered dose).
Metabolism
Tramadol is extensively metabolised after oral administration. The major metabolic pathways appear
to be N - and O -demethylation and glucuronidation or sulfation in the liver. Only O desmethyltramadol (M1) is pharmacologically active. Production of M1 is dependent on the CYP2D6
isoenzyme of cytochrome P450. Patients who metabolize drugs poorly via CYP2D6 may obtain
reduced benefit from Tramadol, due to reduced formation of M1. N-demethylation is catalyzed by the
CYP3A4 isoenzyme of cytochrome P450. The inhibition of one or both types of the isoenzymes
CYP3A4 and CYP2D6 involved in the biotransformation of Tramadol may affect the plasma
concentration of Tramadol or its active metabolite.
Elimination
Mainly the kidneys, with a cumulative renal excretion (Tramadol and metabolites) of approximately
95%, excrete Tramadol and its metabolites. In young adults approximately 15 - 19% of an
administered dose of Tramadol is excreted in the urine as unmetabolised drug. In the elderly, this
increases to about 35%. Biliary excretion is of little importance. In young adults, the half-life of
Tramadol is 5 - 7 h and the half-life of M1 is 6 - 8 h. Total clearance is approximately 430 - 610
mL/min.
Gender: The pharmacokinetics of Tramadol is similar in males and females.
Elderly: In the elderly (age over 75 years), the volume of distribution of Tramadol is decreased by 25%
and clearance is decreased by 40%. As a result, Tramadol Cmax and total exposure are increased by
30% and 50%, respectively, but the half-life of Tramadol is only slightly prolonged (by 15%).
Hepatic Insufficiency & Renal Insufficiency
Elimination of Tramadol and M1 is impaired in patients with hepatic or renal impairment. In patients
with hepatic impairment, the mean half-life of Tramadol was found to be 13 h (range up to 19 h), and
the mean half-life of M1 was 19 h (range up to 36 h). In patients with severe renal impairment
(creatinine clearance < 5 mL/min) the mean half-life of Tramadol was 11 h (range up to 20 h), and the
mean half-life of M1 was 17 h (range up to 43 h).
Indications
Xtram is indicated for the management of moderate to severe, acute, or chronic pain and in painful
diagnostic or therapeutic procedures.
Contraindications
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Tramadol is contraindicated in:
Individuals with known hypersensitivity to Tramadol or any excipients
Acute intoxication with alcohol, hypnotics, analgesics, opioids or psychotropic drugs
Patients who are taking MAO inhibitors or who have taken them within the last 14 days
Known hypersensitivity to opioids
Patients with uncontrolled epilepsy or epilepsy not adequately controlled by treatment.
Tramadol must not be used for narcotic withdrawal treatment.
Adverse Reactions
Adverse reactions that may occur after administration of Tramadol resemble those known to occur
with opioids. Adverse reactions recorded in 13,802 patients from trials with different formulations of
Tramadol. The nature and incidence of reactions (in CIOMS format where very common ≥ 1/10;
common ≥ 1/100 and <1/10; uncommon ≥ 1/1000 and <1/100; rare ≥ 1/10,000 and <1/1000; were as
follows:
Cardiovascular
Uncommon: orthostatic dysregulation (tendency to collapse, and cardiovascular collapse) and
tachycardia, flushing
Rare: increase in blood pressure, bradycardia
Respiratory
Rare: dyspnoea
Gastrointestinal
Very common: nausea
Common: vomiting, constipation
Uncommon: dyspepsia, diarrhea, abdominal pain, flatulence, urge to vomit
Rare: changes in appetite
Neurological
Very common: dizziness
Common: autonomic nervous effects (mainly dry mouth, perspiration), headache sedation, asthenia,
fatigue.
Uncommon: trembling
Rare: changes in mood (usually elevation, occasionally dysphoria) paraesthesia, hallucinations,
confusion, coordination disturbance, sleep disturbance, anxiety, nightmares, motor system weakness,
changes in appetite, tremor, respiratory depression, seizures, involuntary muscle contractions,
changes in activity (usually suppression, occasionally increase), changes in cognitive and sensorial
capacity (eg. decision behavior, perception disorders), syncope
Hypersensitivity and skin
Common: sweating
Uncommon: skin reactions, pruritus, rash
Rare: shock reactions, anaphylaxis, allergic reactions
Genitourinary
Rare: micturition disorders (difficulty in passing urine and urinary retention), dysuria
Special senses
Rare: visual disturbance (blurred vision)
The incidence of "non-specific CNS irritation" (dizziness), "autonomic nervous effects" (perspiration),
"orthostatic dysregulation (tendency to collapse and cardiovascular collapse) and tachycardia and
"nausea/urge to vomit/vomiting" can be increased with rapid intravenous administration and also
tends to be dose dependent. No tests of significance have been performed.
Drug abuse and dependence
Although Tramadol can produce drug dependence of the µ-opioid type (like codeine or
dextropropoxyphene) and potentially may be abused, there has been little evidence of abuse in
clinical experience to date. In clinical trials, Tramadol produced some effects similar to an opioid, and
at supratherapeutic doses was recognized as an opioid in subjective/behavioral studies. Part of the
activity of Tramadol is thought to be derived from its active metabolite, which is responsible for some
delay in onset of activity and some extension of the duration of µ-opioid activity. Delayed µ-opioid
activity is believed to reduce a drug's abuse liability.
On long term treatment (6 months or more) habituation and dependence cannot be rolled out
Tolerance and withdrawal
Tolerance development has been reported to be relatively mild. Symptoms of withdrawal reactions,
similar to those occurring during opiate withdrawal, may occur as follows: agitation, anxiety,
nervousness, insomnia, hyperkinesia, tremor, and gastrointestinal symptoms. Other symptoms that
have very rarely been seen with Tramadol discontinuation include panic attacks, severe anxiety,
hallucinations, paraesthesias, tinnitus, and unusual CNS symptoms.
Warnings and Precautions
Acute abdominal conditions
The administration of Tramadol may complicate the clinical assessment of patients with acute
abdominal conditions.
Respiratory depression
Tramadol should be administered cautiously in patients at risk of respiratory depression.
When large doses of Tramadol are administered with anesthetic medications or alcohol, respiratory
depression may result. Cases of intra-operative respiratory depression, usually with large intravenous
doses of Tramadol and with concurrent administration of respiratory depressants, have been
reported.
Increased intracranial pressure or head trauma
Tramadol should be used with caution in patients with increased intracranial pressure, head injury,
shock, or a reduced level of consciousness of uncertain origin. Pupillary changes (miosis) from
Tramadol may obscure the existence, extent, or course of intracranial pathology. Clinicians should
also maintain a high index of suspicion for adverse drug reaction when evaluating altered mental
status in these patients if they are receiving Tramadol.
Renal and hepatic disease
With the prolonged half-life in these conditions, achievement of steady state is delayed, so that it may
take several days for elevated plasma concentrations to develop.
Renal disease
Impaired renal function results in a decreased rate and extent of excretion of Tramadol and its active
metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosage reduction is
recommended. Tramadol is not recommended in patients with severe renal impairment (creatinine
clearance <10 mL/min). As Tramadol is removed very slowly by haemodialysis or haemofiltration,
post-dialysis administration to maintain analgesia is not usually necessary.
Hepatic disease
Metabolism of Tramadol and M1 is reduced in patients with advanced cirrhosis of the liver. In
cirrhotic patients, dosage reduction is recommended.
Effects on ability to drive and use machinery
Due to its sedative effect, patients should be advised to avoid driving or operating machinery whilst
taking Tramadol.
Patients physically dependent on opioids
Tramadol is not recommended as a substitute in opioid-dependent patients. Although Tramadol is an
opiate-agonist, it cannot suppress opioid withdrawal symptoms. Animal experiments have shown that
under certain circumstances the administration of Tramadol may provoke a withdrawal syndrome in
opioid-dependent monkeys. Because of the difficulty in assessing dependence in patients who have
previously received substantial amounts of opioid medications, caution should be used in the
administration of Tramadol to such patients.
In patients with a tendency for drug abuse or dependence, treatment with Tramadol should only be
carried out for short periods under strict medical supervision.
Cases of dependence and abuse of Tramadol have been reported rarely.
Seizure risk
Convulsions have been reported in patients receiving Tramadol at the recommended dose levels. The
risk may be increased when doses of Tramadol exceed the recommended upper daily dose limit. In
addition, Tramadol may increase the seizure risk in patients taking other medication that lowers the
seizure threshold (see Interactions with other drugs). Patients with epilepsy or those susceptible to
seizures should only be treated with Tramadol if there are compelling circumstances.
Anaphylactoid reactions
Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving Tramadol.
These reactions often occur following the first dose. Other reported reactions include pruritus, hives,
bronchospasm, and angioedema.
Intra-operative use
In one study using nitrous oxide/Tramadol anesthetic technique (with only intermittent
administration of enflurane "as required"), Tramadol was reported to enhance intra-operative recall.
Hence its use during potentially very light levels of general anesthesia should be avoided. Two recent
studies of Tramadol administration during anesthesia comprising continuous administration of
isoflurane did not show clinically significant lightening of anesthetic depth or intra-operative recall.
Therefore, providing the current practice of administering continuous, potent (volatile or intravenous)
anesthetic agent is followed. Tramadol may be used intra-operatively in the same way as other
analgesic agents are routinely used.
Long-term use
Tramadol studied in controlled clinical trials for periods of up to three months. In one smalluncontrolled study, patients with cancer pain received a dose of 150 mg Tramadol per day for up to
six months. Beyond six months, no clinical studies investigating the safety and efficacy of Tramadol
are available.
When Tramadol treatment of pain is required long-term, careful and regular monitoring should be
carried out to establish whether, and to what extent, ongoing treatment is necessary.
Use in pregnancy - Category C
There are no adequate and well-controlled studies with Tramadol in pregnant women; therefore,
Tramadol should not be used during pregnancy. Studies in animals using IV or IM routes of
administration have not been conducted. Tramadol has been shown to be embryotoxic and fetotoxic
in mice, rats and rabbits in maternally toxic doses of 120 mg/kg in mice, or higher in rats and 75
mg/kg in rabbits, but was not teratogenic at these dose levels. No harm to the fetus due to Tramadol
was seen at doses that were not maternally toxic. No drug-related teratogenic effects were observed
in progeny of mice, rats, or rabbits treated with Tramadol (75 mg/kg for rats or 175 mg/kg for
rabbits). Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification
and increased supernumerary ribs at maternally toxic dose levels. Transient delays in development or
behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal
lethality were reported only in one rabbit study at 300 mg/kg, a dose that would cause extreme
maternal toxicity in the rabbit.
In peri- and post-natal studies in rats, progeny of dams receiving oral (gavage) dose levels of 50 mg/kg
or greater had decreased weights and pup survival was decreased early in lactation at 80 mg/kg (6-10
times the maximum human dose). No toxicity was observed for progeny of dams receiving 8, 10, 20,
25 or 40 mg/kg. Maternal toxicity was observed at all dose levels.
Labour and Delivery
Tramadol should not be used in pregnant women prior to or during labour unless the potential
benefits outweigh the potential risks, because safe use in pregnancy has not been established.
Chronic use during pregnancy may lead to neonatal withdrawal symptoms. If Tramadol were to be
used during labour, it may cause respiratory depression in the newborn. Tramadol has been shown to
cross the placenta. The mean ratio of serum Tramadol in the umbilical veins compared to maternal
veins was 0.83 for 40 women given Tramadol during labour.
The effect of Tramadol, if any, on the later growth, development, and functional maturation of the
child is unknown.
Use in lactation
Tramadol is not recommended during breast-feeding, because its safety in infants and newborns has
not been studied. Low levels of Tramadol have been detected in breast milk. Following a single
intravenous 100 mg dose of Tramadol, the cumulative excretion in breast milk within 16 hours postdose was 100 μg of Tramadol (0.1% of the maternal dose) and 27 μg of M1.
Drug Interactions
Use with CNS depressants - Tramadol should be used with caution and in reduced dosages when
administered to patients receiving CNS depressants such as alcohol, opioids, anesthetic agents,
phenothiazines, tranquillizers, or sedative hypnotics.
The combination of Tramadol with mixed opiate agonists/antagonists (eg. buprenorphine,
pentazocine) is not advisable because the analgesic effect of a pure agonist may be theoretically
reduced in such circumstances.
Use with other serotonergic agents - the presence of another drug that increases serotonin by any
mechanism should alert the treating physician to the possibility of an interaction. In isolated cases,
there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of
tramadol in combination with other serotonergic medicines such as selective serotonin re-uptake
inhibitors (SSRIs). Signs of serotonin syndrome may be, for example, confusion, agitation, fever,
sweating, ataxia, hyperreflexia, myoclonus, and diarrhea. Withdrawal of the serotonergic medicines
usually brings about a rapid improvement. Drug treatment depends on the nature and severity of the
symptoms.
Use with coumarin derivatives - caution should be exercised during concomitant treatment with
Tramadol and coumarin derivatives (eg. warfarin) due to reports of increased international
normalized ratio (INR) with major bleeding and ecchymoses in some patients.
Drugs that reduce the seizure threshold - Tramadol can induce convulsions and increase the potential
for selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics and other seizure
threshold lowering agents to cause convulsions.
Use with MAO inhibitors - Tramadol should not be used in patients who are taking MAO inhibitors or
who have taken them within the last fourteen days, as Tramadol inhibits the uptake of noradrenaline
and serotonin.
Other interactions - Tramadol does not appear to induce its own metabolism in humans, since
observed maximal plasma concentrations after multiple oral doses are higher than expected based on
single-dose data. Tramadol is a mild inducer of selected drug metabolism pathways measured in
animals.
Concomitant administration of Tramadol with carbamazepine causes a significant increase in
Tramadol metabolism, presumably through metabolic induction by carbamazepine. Patients receiving
chronic carbamazepine doses of up to 800 mg daily may require up to twice the recommended dose
of Tramadol.
Tramadol is metabolised to M1 by the CYP2D6 P450 isoenzyme. Drugs that selectively inhibit that
isoenzyme (quinidine, phenothiazines, and antipsychotic agents) may cause increased concentrations
of Tramadol and decreased concentrations of M1. The clinical consequences of these potential effects
a fully investigated.
Concomitant administration of Tramadol with cimetidine does not result in clinically significant
changes in Tramadol pharmacokinetics. Therefore, no alteration of the Tramadol dosage regimen is
recommended.
Other drugs known to inhibit the CYP3A4 isoenzyme of cytochrome P450, such as ketoconazole and
erythromycin, may inhibit the metabolism of Tramadol (via N-demethylation) and probably the
metabolism of the active O-demethylated metabolite (M1). The clinical importance of such an
interaction has not been studied.
In a limited number of studies, the pre- or post-operative application of the antiemetic 5-HT3
antagonist ondansetron increased the requirement of Tramadol in patients with postoperative pain.
Dosage and Administration
The dose of Tramadol should be titrated to the severity of the pain and the clinical response of the
individual patient. Tramadol approved for use in adults, adolescents, and children over the age of 2
years
Oral administration - For the treatment of moderate pain XTram, 50 - 100 mg administered two or
three times daily may be sufficient. XTram 50 mg may be adequate as the initial dose for moderate
pain.
For moderate to severe pain, 50 - 100 mg as needed for relief, every four to six hours may be
administered.
Tramadol 100 mg is usually more effective as the initial dose for more severe pain.
The maximum daily dose should not exceed 400 mg per day.
Uses in the elderly - in subjects over the age of 75 years, serum concentrations are slightly elevated
and the elimination half-life is slightly prolonged. Subjects in this age group are also expected to vary
more widely in their ability to tolerate adverse drug effects. Daily doses in excess of 300 mg are not
recommended in patients over 75 years.
Renal insufficiency - impaired renal function results in a decreased rate and extent of excretion of
Tramadol and M1. In patients with creatinine clearances of less than 30 mL/min, adjustment of the
dosage regimen is recommended. In these patients, the dosage interval of Tramadol should be
increased to 12 hours. Since only 7% of an administered dose is removed by haemodialysis, dialysis
patients can receive their regular dose on the day of dialysis. Tramadol is not recommended in
patients with severe renal impairment (creatinine clearance <10 mL/min.).
Hepatic insufficiency - In hepatic impairment, the initial oral dose of Tramadol is 50 mg of the
immediate release formulation. Depending on the severity of the impairment and individual clinical
response, the recommended dosage interval (4-6 hours) may require to be extended, and/or the dose
level titrated as required.
Over Dosage
Few cases of overdose with Tramadol have been reported.
Symptoms
Symptoms of overdosage with Tramadol are similar to those of other centrally acting analgesics
(opioids) and include miosis, vomiting, cardiovascular collapse, consciousness disorders including
coma, convulsions, respiratory depression and respiratory arrest.
Treatment
Should overdosage occur, general emergency measures should be implemented? Keep the
respiratory airways open, and maintain respiration and circulation. If overdosage is due to ingestion
of an oral dose form, emptying the stomach by gastric lavage should be considered because of the
possibility of ongoing release in the stomach.
Activated charcoal may reduce absorption of the drug if given within 1-2 hours after ingestion. In
patients who are not fully conscious or have impaired gag reflex, considerations should be given to
administering activated charcoal via a nasogastric tube, once the airway is protected.
Naloxone will reverse respiratory depression, but not all symptoms caused by overdosage with
Tramadol. Convulsions occurring in mice following the administration of toxic doses of Tramadol
could be suppressed with barbiturates or benzodiazepines, but were increased with naloxone. If
convulsions are observed, diazepam should be given intravenously. Naloxone did not change the
lethality of an overdose in mice.
Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore,
treatment of overdosage with Tramadol with haemodialysis or haemofiltration alone is not suitable
for detoxification.
Presentation
XTram 50 mg capsule
Box of 10 capsules